tbuckley/cabot-search huggingface dataset:
Cardiopulmonary exercise testing during follow-up after acute pulmonary embolism
Authors: Ioannis T. Farmakis, Luca Valerio, Stefano Barco, Eva Alsheimer, Ralf Ewert, George Giannakoulas, Lukas Hobohm, Karsten Keller, Anna C. Mavromanoli, Stephan Rosenkranz, Timothy A. Morris, Stavros V. Konstantinides, Matthias Held, Daniel Dumitrescu
Journal: European Respiratory Journal (2023)

Background Cardiopulmonary exercise testing (CPET) may provide prognostically valuable information during follow-up after pulmonary embolism (PE). Our objective was to investigate the association of patterns and degree of exercise limitation, as assessed by CPET, with clinical, echocardiographic and laboratory abnormalities and quality of life (QoL) after PE. Methods In a prospective cohort study of unselected consecutive all-comers with PE, survivors of the index acute event underwent 3- and 12-month follow-ups, including CPET. We defined cardiopulmonary limitation as ventilatory inefficiency or insufficient cardiocirculatory reserve. Deconditioning was defined as peak O 2 uptake ( V ′ O 2 ) &lt;80% with no other abnormality. Results Overall, 396 patients were included. At 3 months, prevalence of cardiopulmonary limitation and deconditioning was 50.1% (34.7% mild/moderate; 15.4% severe) and 12.1%, respectively; at 12 months, it was 44.8% (29.1% mild/moderate; 15.7% severe) and 14.9%, respectively. Cardiopulmonary limitation and its severity were associated with age (OR per decade 2.05, 95% CI 1.65–2.55), history of chronic lung disease (OR 2.72, 95% CI 1.06–6.97), smoking (OR 5.87, 95% CI 2.44–14.15) and intermediate- or high-risk acute PE (OR 4.36, 95% CI 1.92–9.94). Severe cardiopulmonary limitation at 3 months was associated with the prospectively defined, combined clinical-haemodynamic end-point of “post-PE impairment” (OR 6.40, 95% CI 2.35–18.45) and with poor disease-specific and generic health-related QoL. Conclusions Abnormal exercise capacity of cardiopulmonary origin is frequent after PE, being associated with clinical and haemodynamic impairment as well as long-term QoL reduction. CPET can be considered for selected patients with persisting symptoms after acute PE to identify candidates for closer follow-up and possible therapeutic interventions.
Targeting the mevalonate pathway suppresses ARID1A-inactivated cancers by promoting pyroptosis
Authors: Wei Zhou, Heng Liu, Zhe Yuan, Joseph Zundell, Martina Towers, Jianhuang Lin, Simona Lombardi, Hao Nie, Brennah Murphy, Tyler Yang, Chen Wang, Liping Liao, Aaron R. Goldman, Toshitha Kannan, Andrew V. Kossenkov, Ronny Drapkin, Luis J. Montaner, Daniel T. Claiborne, Nan Zhang, Shuai Wu, Rugang Zhang
Journal: Cancer Cell (2023)
Air pollution and COPD: GOLD 2023 committee report
Authors: Don D. Sin, Dany Doiron, Alvar Agusti, Antonio Anzueto, Peter J. Barnes, Bartolome R. Celli, Gerard J. Criner, David Halpin, MeiLan K. Han, Fernando J. Martinez, Maria Montes de Oca, Alberto Papi, Ian Pavord, Nicolas Roche, Dave Singh, Robert Stockley, M. Victorina Lopez Varlera, Jadwiga Wedzicha, Claus Vogelmeier, Jean Bourbeau
Journal: European Respiratory Journal (2023)

Exposure to air pollution is a major contributor to the pathogenesis of COPD worldwide. Indeed, most recent estimates suggest that 50% of the total attributable risk of COPD may be related to air pollution. In response, the Global Initiative for Chronic Obstructive Lung Disease (GOLD) Scientific Committee performed a comprehensive review on this topic, qualitatively synthesised the evidence to date and proffered recommendations to mitigate the risk. The review found that both gaseous and particulate components of air pollution are likely contributors to COPD. There are no absolutely safe levels of ambient air pollution and the relationship between air pollution levels and respiratory events is supra-linear. Wildfires and extreme weather events such as heat waves, which are becoming more common owing to climate change, are major threats to COPD patients and acutely increase their risk of morbidity and mortality. Exposure to air pollution also impairs lung growth in children and as such may lead to developmental COPD. GOLD recommends strong public health policies around the world to reduce ambient air pollution and for implementation of public warning systems and advisories, including where possible the use of personalised apps, to alert patients when ambient air pollution levels exceed acceptable minimal thresholds. When household particulate content exceeds acceptable thresholds, patients should consider using air cleaners and filters where feasible. Air pollution is a major health threat to patients living with COPD and actions are urgently required to reduce the morbidity and mortality related to poor air quality around the world.
Tuberculosis Outbreak in a State Prison System — Washington, 2021–2022
Authors: Randy M. Stalter, Monica Pecha, Lana Dov, David Miller, Zainab Ghazal, Jonathan Wortham, Sandy Althomsons, Molly Deutsch-Feldman, Rebekah Stewart, Derrick Felix, Sophia Hsu, Lara B. Strick
Journal: MMWR Morbidity and Mortality Weekly Report (2023)

During 2014-2020, no tuberculosis (TB) cases were reported within the Washington state prison system. However, during July 2021-June 2022, 25 TB cases were reported among persons incarcerated or formerly incarcerated in two Washington state prisons. Phylogenetic analyses of whole genome sequencing data indicated that Mycobacterium tuberculosis isolates from all 11 patients with culture-confirmed TB were closely related, suggesting that these cases represented a single outbreak. The median infectious period for 12 patients who were considered likely contagious was 170 days. As of November 15, 2022, the Washington State Department of Corrections (WADOC) and Washington State Department of Health (WADOH), with technical assistance from CDC, had identified 3,075 contacts among incarcerated residents and staff members at five state prisons, and 244 contacts without a known TB history received a diagnosis of latent TB infection (LTBI). Persons who were evaluated for TB disease were isolated; those receiving a diagnosis of TB then initiated antituberculosis therapy. Persons with LTBI were offered treatment to prevent progression to TB disease. This ongoing TB outbreak is the largest in Washington in 20 years. Suspension of annual TB screening while limited resources were redirected toward the COVID-19 response resulted in delayed case detection that facilitated TB transmission. In addition, fear of isolation might discourage residents and staff members from reporting symptoms, which likely also leads to delayed TB diagnoses. Continued close collaboration between WADOC and WADOH is needed to end this outbreak and prevent future outbreaks.
Rituximab versus azathioprine for maintenance of remission for patients with ANCA-associated vasculitis and relapsing disease: an international randomised controlled trial
Authors: Rona M Smith, Rachel B Jones, Ulrich Specks, Simon Bond, Marianna Nodale, Reem Al-jayyousi, Jacqueline Andrews, Annette Bruchfeld, Brian Camilleri, Simon Carette, Chee Kay Cheung, Vimal Derebail, Tim Doulton, Alastair Ferraro, Lindsy Forbess, Shouichi Fujimoto, Shunsuke Furuta, Ora Gewurz-Singer, Lorraine Harper, Toshiko Ito-Ihara, Nader Khalidi, Rainer Klocke, Curry Koening, Yoshinori Komagata, Carol Langford, Peter Lanyon, Raashid Luqmani, Carol McAlear, Larry W Moreland, Kim Mynard, Patrick Nachman, Christian Pagnoux, Chen Au Peh, Charles Pusey, Dwarakanathan Ranganathan, Rennie L Rhee, Robert Spiera, Antoine G Sreih, Vladamir Tesar, Giles Walters, Caroline Wroe, David Jayne, Peter A Merkel
Journal: Annals of the Rheumatic Diseases (2023)

Objective Following induction of remission with rituximab in anti-neutrophil cytoplasmic antibody-associated vasculitis (AAV) relapse rates are high, especially in patients with history of relapse. Relapses are associated with increased exposure to immunosuppressive medications, the accrual of damage and increased morbidity and mortality. The RITAZAREM trial compared the efficacy of repeat-dose rituximab to daily oral azathioprine for prevention of relapse in patients with relapsing AAV in whom remission was reinduced with rituximab. Methods RITAZAREM was an international randomised controlled, open-label, superiority trial that recruited 188 patients at the time of an AAV relapse from 29 centres in seven countries between April 2013 and November 2016. All patients received rituximab and glucocorticoids to reinduce remission. Patients achieving remission by 4 months were randomised to receive rituximab intravenously (1000 mg every 4 months, through month 20) (85 patients) or azathioprine (2 mg/kg/day, tapered after month 24) (85 patients) and followed for a minimum of 36 months. The primary outcome was time to disease relapse (either major or minor relapse). Results Rituximab was superior to azathioprine in preventing relapse: HR 0.41; 95% CI 0.27 to 0.61, p&lt;0.001. 19/85 (22%) patients in the rituximab group and 31/85 (36%) in the azathioprine group experienced at least one serious adverse event during the treatment period. There were no differences in rates of hypogammaglobulinaemia or infection between groups. Conclusions Following induction of remission with rituximab, fixed-interval, repeat-dose rituximab was superior to azathioprine for preventing disease relapse in patients with AAV with a prior history of relapse. Trial registration number NCT01697267 ; ClinicalTrials.gov identifier
Faecal metabolome and its determinants in inflammatory bowel disease
Authors: Arnau Vich Vila, Shixian Hu, Sergio Andreu-Sánchez, Valerie Collij, Bernadien H Jansen, Hannah E Augustijn, Laura A Bolte, Renate A A A Ruigrok, Galeb Abu-Ali, Cosmas Giallourakis, Jessica Schneider, John Parkinson, Amal Al-Garawi, Alexandra Zhernakova, Ranko Gacesa, Jingyuan Fu, Rinse K Weersma
Journal: Gut (2023)

Objective Inflammatory bowel disease (IBD) is a multifactorial immune-mediated inflammatory disease of the intestine, comprising Crohn’s disease and ulcerative colitis. By characterising metabolites in faeces, combined with faecal metagenomics, host genetics and clinical characteristics, we aimed to unravel metabolic alterations in IBD. Design We measured 1684 different faecal metabolites and 8 short-chain and branched-chain fatty acids in stool samples of 424 patients with IBD and 255 non-IBD controls. Regression analyses were used to compare concentrations of metabolites between cases and controls and determine the relationship between metabolites and each participant’s lifestyle, clinical characteristics and gut microbiota composition. Moreover, genome-wide association analysis was conducted on faecal metabolite levels. Results We identified over 300 molecules that were differentially abundant in the faeces of patients with IBD. The ratio between a sphingolipid and L-urobilin could discriminate between IBD and non-IBD samples (AUC=0.85). We found changes in the bile acid pool in patients with dysbiotic microbial communities and a strong association between faecal metabolome and gut microbiota. For example, the abundance of Ruminococcus gnavus was positively associated with tryptamine levels. In addition, we found 158 associations between metabolites and dietary patterns, and polymorphisms near NAT2 strongly associated with coffee metabolism. Conclusion In this large-scale analysis, we identified alterations in the metabolome of patients with IBD that are independent of commonly overlooked confounders such as diet and surgical history. Considering the influence of the microbiome on faecal metabolites, our results pave the way for future interventions targeting intestinal inflammation.
Tumors evade immune cytotoxicity by altering the surface topology of NK cells
Authors: Xiaohu Zheng, Zhuanghao Hou, Yeben Qian, Yongwei Zhang, Quanwei Cui, Xuben Wang, Yiqing Shen, Zhenbang Liu, Yonggang Zhou, Binqing Fu, Rui Sun, Zhigang Tian, Guangming Huang, Haiming Wei
Journal: Nature Immunology (2023)
How autoreactive thymocytes differentiate into regulatory versus effector CD4+ T cells after avoiding clonal deletion
Authors: Xuguang Tai, Alyssa Indart, Mirelle Rojano, Jie Guo, Nicolai Apenes, Tejas Kadakia, Marco Craveiro, Amala Alag, Ruth Etzensperger, Mohamed Elsherif Badr, Flora Zhang, Zhongmei Zhang, Jie Mu, Terry Guinter, Assiatu Crossman, Larry Granger, Susan Sharrow, Xuyu Zhou, Alfred Singer
Journal: Nature Immunology (2023)

Abstract Thymocytes bearing autoreactive T cell receptors (TCRs) are agonist-signaled by TCR/co-stimulatory molecules to either undergo clonal deletion or to differentiate into specialized regulatory T (T reg ) or effector T (T eff ) CD4 + cells. How these different fates are achieved during development remains poorly understood. We now document that deletion and differentiation are agonist-signaled at different times during thymic selection and that T reg and T eff cells both arise after clonal deletion as alternative lineage fates of agonist-signaled CD4 + CD25 + precursors. Disruption of agonist signaling induces CD4 + CD25 + precursors to initiate Foxp3 expression and become T reg cells, whereas persistent agonist signaling induces CD4 + CD25 + precursors to become IL-2 + T eff cells. Notably, we discovered that transforming growth factor-β induces Foxp3 expression and promotes T reg cell development by disrupting weaker agonist signals and that Foxp3 expression is not induced by IL-2 except under non-physiological in vivo conditions. Thus, TCR signaling disruption versus persistence is a general mechanism of lineage fate determination in the thymus that directs development of agonist-signaled autoreactive thymocytes.
Dual genetic tracing reveals a unique fibroblast subpopulation modulating cardiac fibrosis
Authors: Maoying Han, Zixin Liu, Lei Liu, Xiuzhen Huang, Haixiao Wang, Wenjuan Pu, Enci Wang, Xiuxiu Liu, Yan Li, Lingjuan He, Xufeng Li, Jiayu Wu, Lin Qiu, Ruling Shen, Qing-Dong Wang, Yong Ji, Reza Ardehali, Qiang Shu, Kathy O. Lui, Lixin Wang, Bin Zhou
Journal: Nature Genetics (2023)
Ascending neurons convey behavioral state to integrative sensory and action selection brain regions
Authors: Chin-Lin Chen, Florian Aymanns, Ryo Minegishi, Victor D. V. Matsuda, Nicolas Talabot, Semih Günel, Barry J. Dickson, Pavan Ramdya
Journal: Nature Neuroscience (2023)

Knowing one's own behavioral state has long been theorized as critical for contextualizing dynamic sensory cues and identifying appropriate future behaviors. Ascending neurons (ANs) in the motor system that project to the brain are well positioned to provide such behavioral state signals. However, what ANs encode and where they convey these signals remains largely unknown. Here, through large-scale functional imaging in behaving animals and morphological quantification, we report the behavioral encoding and brain targeting of hundreds of genetically identifiable ANs in the adult fly, Drosophila melanogaster. We reveal that ANs encode behavioral states, specifically conveying self-motion to the anterior ventrolateral protocerebrum, an integrative sensory hub, as well as discrete actions to the gnathal ganglia, a locus for action selection. Additionally, AN projection patterns within the motor system are predictive of their encoding. Thus, ascending populations are well poised to inform distinct brain hubs of self-motion and ongoing behaviors and may provide an important substrate for computations that are required for adaptive behavior.
Urea cycle activation triggered by host-microbiota maladaptation driving colorectal tumorigenesis
Authors: Haoyan Chen, Tianying Tong, Shi-Yuan Lu, Linhua Ji, Baoqin Xuan, Gang Zhao, Yuqing Yan, Linhong Song, Licong Zhao, Yile Xie, Xiaoxu Leng, Xinyu Zhang, Yun Cui, Xiaoyu Chen, Hua Xiong, TaChung Yu, Xiaobo Li, Tiantian Sun, Zheng Wang, Jinxian Chen, Ying-Xuan Chen, Jie Hong, Jing-Yuan Fang
Journal: Cell Metabolism (2023)
Neutralizing IL-8 potentiates immune checkpoint blockade efficacy for glioma
Authors: Haofei Liu, Qiwen Zhao, Leyong Tan, Xin Wu, Rui Huang, Yonglin Zuo, Longjuan Chen, Jigui Yang, Zuo-Xin Zhang, Wenchen Ruan, Jiayang Wu, Fei He, Yiliang Fang, Fangyuan Mao, Peipei Zhang, Xiaoning Zhang, Peidi Yin, Zexuan Yan, Wenwen Xu, Huimin Lu, Qingrui Li, Mei Liang, Yanjun Jia, Cong Chen, Senlin Xu, Yu Shi, Yi-Fang Ping, Guang-Jie Duan, Xiao-Hong Yao, Zhijian Han, Tao Pang, Youhong Cui, Xia Zhang, Bo Zhu, Chunjian Qi, Yan Wang, Sheng-Qing Lv, Xiu-Wu Bian, Xindong Liu
Journal: Cancer Cell (2023)

Malignant gliomas are largely refractory to immune checkpoint blockade (ICB) therapy. To explore the underlying immune regulators, we examine the microenvironment in glioma and find that tumor-infiltrating T cells are mainly confined to the perivascular cuffs and express high levels of CCR5, CXCR3, and programmed cell death protein 1 (PD-1). Combined analysis of T cell clustering with T cell receptor (TCR) clone expansion shows that potential tumor-killing T cells are mainly categorized into pre-exhausted/exhausted and effector CD8+ T subsets, as well as cytotoxic CD4+ T subsets. Notably, a distinct subpopulation of CD4+ T cells exhibits innate-like features with preferential interleukin-8 (IL-8) expression. With IL-8-humanized mouse strain, we demonstrate that IL-8-producing CD4+ T, myeloid, and tumor cells orchestrate myeloid-derived suppressor cell infiltration and angiogenesis, which results in enhanced tumor growth but reduced ICB efficacy. Antibody-mediated IL-8 blockade or the inhibition of its receptor, CXCR1/2, unleashes anti-PD-1-mediated antitumor immunity. Our findings thus highlight IL-8 as a combinational immunotherapy target for glioma.
Somatic mutations alter the differentiation outcomes of iPSC-derived neurons
Authors: Pau Puigdevall, Julie Jerber, Petr Danecek, Sergi Castellano, Helena Kilpinen
Journal: Cell Genomics (2023)

The use of induced pluripotent stem cells (iPSC) as models for development and human disease has enabled the study of otherwise inaccessible tissues. A remaining challenge in developing reliable models is our limited understanding of the factors driving irregular differentiation of iPSCs, particularly the impact of acquired somatic mutations. We leveraged data from a pooled dopaminergic neuron differentiation experiment of 238 iPSC lines profiled with single-cell RNA and whole-exome sequencing to study how somatic mutations affect differentiation outcomes. We found that deleterious somatic mutations in key developmental genes, notably the
Genetic dissection of the pluripotent proteome through multi-omics data integration
Authors: Selcan Aydin, Duy T. Pham, Tian Zhang, Gregory R. Keele, Daniel A. Skelly, Joao A. Paulo, Matthew Pankratz, Ted Choi, Steven P. Gygi, Laura G. Reinholdt, Christopher L. Baker, Gary A. Churchill, Steven C. Munger
Journal: Cell Genomics (2023)

Genetic background drives phenotypic variability in pluripotent stem cells (PSCs). Most studies to date have used transcript abundance as the primary molecular readout of cell state in PSCs. We performed a comprehensive proteogenomics analysis of 190 genetically diverse mouse embryonic stem cell (mESC) lines. The quantitative proteome is highly variable across lines, and we identified pluripotency-associated pathways that were differentially activated in the proteomics data that were not evident in transcriptome data from the same lines. Integration of protein abundance to transcript levels and chromatin accessibility revealed broad co-variation across molecular layers as well as shared and unique drivers of quantitative variation in pluripotency-associated pathways. Quantitative trait locus (QTL) mapping localized the drivers of these multi-omic signatures to genomic hotspots. This study reveals post-transcriptional mechanisms and genetic interactions that underlie quantitative variability in the pluripotent proteome and provides a regulatory map for mESCs that can provide a basis for future mechanistic studies.
Epithelial cells activate fibroblasts to promote esophageal cancer development
Authors: Yamei Chen, Shihao Zhu, Tianyuan Liu, Shaosen Zhang, Junting Lu, Wenyi Fan, Lin Lin, Tao Xiang, Jie Yang, Xuan Zhao, Yiyi Xi, Yuling Ma, Guoyu Cheng, Dongxin Lin, Chen Wu
Journal: Cancer Cell (2023)
Adaptation of transgene mRNA translation boosts the anticancer efficacy of oncolytic HSV1
Authors: Huy-Dung Hoang, Aida Said, Nasana Vaidya, Victoria H Gilchrist, Kyle Malone, Usha Kabilan, Serena Topshee, Xiao Xiang, An-Dao Yang, David Olagnier, Karen Mossman, Shawn T Beug, Seyed Mehdi Jafarnejad, Samuel T Workenhe, Tyson E Graber, Tommy Alain
Journal: Journal for ImmunoTherapy of Cancer (2023)

Transgenes deliver therapeutic payloads to improve oncolytic virus immunotherapy. Transgenes encoded within oncolytic viruses are designed to be highly transcribed, but protein synthesis is often negatively affected by viral infection, compromising the amount of therapeutic protein expressed. Studying the oncolytic herpes simplex virus-1 (HSV1), we found standard transgene mRNAs to be suboptimally translated in infected cells. Using RNA-Seq reads, we determined the transcription start sites and 5'leaders of HSV1 genes and uncovered the US11 5'leader to confer superior activity in translation reporter assays. We then incorporated this 5'leader into GM-CSF expression cassette in oncolytic HSV1 and compared the translationally adapted oncolytic virus with the conventional, leaderless, virus in vitro and in mice. Inclusion of the US11 5'leader in the GM-CSF transgene incorporated into HSV1 boosted translation in vitro and in vivo. Importantly, treatment with US11 5'leader-GM-CSF oncolytic HSV1 showed superior antitumor immune activity and improved survival in a syngeneic mouse model of colorectal cancer as compared with leaderless-GM-CSF HSV1. Our study demonstrates the therapeutic value of identifying and integrating platform-specific cis-acting sequences that confer increased protein synthesis on transgene expression.
Common multi-day rhythms in smartphone behavior
Authors: Enea Ceolini, Arko Ghosh
Journal: npj Digital Medicine (2023)

The idea that abnormal human activities follow multi-day rhythms is found in ancient beliefs on the moon to modern clinical observations in epilepsy and mood disorders. To explore multi-day rhythms in healthy human behavior our analysis includes over 300 million smartphone touchscreen interactions logging up to 2 years of day-to-day activities (N401 subjects). At the level of each individual, we find a complex expression of multi-day rhythms where the rhythms occur scattered across diverse smartphone behaviors. With non-negative matrix factorization, we extract the scattered rhythms to reveal periods ranging from 7 to 52 days - cutting across age and gender. The rhythms are likely free-running - instead of being ubiquitously driven by the moon - as they did not show broad population-level synchronization even though the sampled population lived in northern Europe. We propose that multi-day rhythms are a common trait, but their consequences are uniquely experienced in day-to-day behavior.